Advanced Healthcare Materials最新文献

Redox imbalance, including excessive production of reactive oxygen species (ROS) caused by mitochondrial dysfunction and insufficient endogenous antioxidant capacity, is the primary cause of myocardial ischemia‒reperfusion (I/R) injury. In the exploration of reducing myocardial I/R injury, it is found that protecting myocardial mitochondrial function after reperfusion not only reduces ROS bursts but also inhibits cell apoptosis triggered by the release of cytochrome c. Additionally, nuclear factor erythroid 2-related factor 2 (Nrf2) is considered a potential therapeutic target for treating myocardial I/R injury by enhancing the cellular antioxidant capacity through the induction of endogenous antioxidant enzymes. In this study, a peptide‒drug conjugate OI-FFG-ss-SS31(ISP) is developed by integrating the Nrf2 activator 4-octyl itaconate (OI) and the mitochondria-targeting protective peptide elamipretide (SS31), and its therapeutic potential for myocardial I/R injury is explored. The results showed that ISP could self-assemble into nanofibers in response to the acidic microenvironment and bind to Keap-1 with high affinity, thereby activating Nrf2 and enhancing antioxidant capacity. Simultaneously, the release of SS31 could improve mitochondrial function and reduce ROS, ultimately providing a restoration of redox homeostasis to effectively alleviate myocardial I/R injury. This study presents a promising acid-triggered peptide-drug conjugate for treating myocardial I/R injury.

Glucocorticoids (GCs) are standard-of-care treatments for inflammatory and immune disorders, and their long-term use increases the risk of osteoporosis. Although GCs decrease bone functionality, their role in bone microvasculature is incompletely understood. Herein, the study investigates the mechanisms of bone microvascular barrier function via osteoblast-endothelial interactions in response to GCs. The animal data shows that prednisolone (Psl) downregulated the osteoblast function and microvessel number and size. To investigate the role of GCs in bone endothelial barrier function further, a bicellular microfluidic in vitro system is developed and utilized, which consists of three-dimensional (3D) perfusable microvascular structures embedded in collagen I/osteoblast matrix. Interestingly, it is demonstrated that GCs significantly inhibit osteogenesis and microvascular barrier function by interfering with endothelial-osteoblast interactions. This effect is triggered by MAPK-induced phosphorylation of connexin43 (Cx43) at Ser282. Collectively, this study sheds light on microvascular function in bone disorders, as osteoporosis, and permits to capture dynamic changes in endothelial-bone interactions under GCs by dissecting the MAPK/Cx43 mechanism and proposing this as a potential target for bone diseases.

Introducing multiple physical cues to control cell behaviors effectively is considered as a promising strategy in developing bioactive wound dressings. Silk nanofiber-based cryogels are developed to favor angiogenesis and tissue regeneration through tuning hydrated state, microporous structure, and mechanical property, but remained a challenge to endow with more physical cues. Here, β-sheet rich silk nanofibers are used to develop cryogels with nanopore structure. Through optimizing crosslinking time and exposing the reactive group inside the nanofibers, the crosslinking reaction is improved to induce stable cryogel formation. Besides the hydrated state and macroporous structure, the nanopore structure formed on the macroporous walls, providing hierarchical microstructures to improve cell migration. Both in vitro and in vivo results reveal quicker cell migration inside the cryogels, which then accelerates angiogenesis and wound healing. The mechanical properties can further regulate to match with skin regeneration. The wound healing study in vivo reveals lower inflammatory factor secretion in the wounds treated with softer cryogels with nanopores, which then resulted in the best angiogenesis and wound healing with less scar. Therefore, the porous cryogels with multiple physical cues can be fabricated with silk nanofibers to control cell behaviors and tissue regeneration, providing a promising approach for designing bioactive wound dressings.

Mimicking compositions and structures of extracellular matrix is widely studied to create in vitro tumor models, to deepen the understanding of the pathogenesis of the different types of cancer, and to identify new therapies. On the other hand, the use of synthetic materials to modulate cancer cell biology and, possibly, to reduce the malignancy of cancer cells through their exploitation is far less explored. Here, the study evaluates the effects of Liquid Crystalline Networks (LCNs) based scaffolds on the growth of A375 metastatic melanoma cells. Interestingly, cells grown on such materials show reduced cell proliferation and colony-forming capacity with respect to those cultivated on standard plates. These effects are associated with a higher percentage of senescent cells and a shift to a more epithelial phenotype, pointing to the occurrence of a mesenchymal to epithelial transition. All these biological outcomes are affected by the amount of crosslinker in the material and have been induced only thanks to the interactions with the polymeric substrate without the need of further chemical (e.g., specific growth factor) or physical (e.g., irradiation) stimuli, opening to the possible development of anti-cancer coatings.

Photosensitizers (PSs) featuring type I reactive oxygen species (ROS) generation and aggregation-induced emission (AIE) activity offer a promising solution to achieve non-invasive and precise theranostics. However, the reported AIE luminogens (AIEgens) with both AIE characteristic and strong type-I ROS generation are still scarce and the structure-property relationship is still unclear. Herein, an innovative acceptor elongation boosted intersystem crossing (AEBIC) design strategy has been proposed to endow the AIEgen strong type-I ROS producibility. The results indicate that the obtained AIEgen exhibit type-I ROS and aggregation-enhanced ROS efficacy, which has been verified by both experimental and theoretical results. Mechanistic study reveal that the acceptor elongation has promoted a dual-channel intersystem crossing pathway to enhance the intersystem crossing (ISC) process due to the differences in triplet configurations, which can be further amplified by aggregation. The afforded type-I AIE-PS show lipid droplet-anchored characteristic and can induce the ferroptosis through destroying the cellular redox homeostasis and increasing lethal levels of lipid peroxidation. Finally, targeting ferroptosis-based cancer therapy can be realized with excellent anti-tumor effect.

Dry eye disease (DED) is a multifaceted ocular surface disorder that significantly impacts patients' daily lives and imposes a substantial economic burden on society. Oxidative stress, induced by the overproduction of reactive oxygen species (ROS), is a critical factor perpetuating the inflammatory cycle in DED. Effectively scavenging ROS is essential to impede the progression of DED. In this study, boronophenylalanine- containing polydopamine (PDA-PBA) nanoparticles are developed loaded with melatonin (MT), which are blended with poly(vinyl alcohol) (PVA) to create eye drops PVA/ PDA-PBA@MT (PPP@MT). In vitro and in vivo studies demonstrate that PPP@MT exhibits dual functionalities in reducing ROS production and downregulating inflammatory pathways, thereby preserving mitochondrial integrity and further inhibiting programmed cell death. Following PPP@MT treatment, tear secretion, corneal structure, and the number of goblet cells are markedly restored in a mouse model of dry eye, indicating the therapeutic efficacy of this agent. Collectively, PPP@MT, characterized by minimal side effects and favorable bioavailability, offers promising therapeutic insights for the management of DED and other ROS-mediated disorders.

Anterior cervical spine surgeries are often complicated by difficulty swallowing due to local postoperative swelling, pain, scarring, and tissue dysfunction. These postoperative events lead to systemic steroid and narcotic use. Local, sustained drug delivery may address these problems, but current materials are unsafe for tight surgical spaces due to high biomaterial swelling, especially upon degradation. To address these shortcomings, a low-swelling, amphiphilic hydrogel system termed DexaPatch is developed containing dexamethasone-poly(lactic-co-glycolic acid) (PLGA) microparticles for sustained release upon local implantation in the surgical site. The bulk amphiphilic hydrogel, comprised of 4-arm poly(ethylene glycol) (PEG)-maleimide macromer cross-linked with triblock dithiolated PEG-poly(propylene glycol)-PEG (poloxamer a.k.a. Pluronic), achieves consistent and tunable mechanical and low-swelling properties. Dexamethasone is released in a burst, followed by a sustained release over 40 days, similar to the release from microparticles alone. The DexaPatch system is lyophilized for shelf stability and surgical handling properties, sterilized, and briefly rehydrated in the operating room prior to surgical implantation in a rabbit model of anterior spinal surgery. DexaPatch results in significantly reduced prevertebral edema radiographically and decreased fibrosis in prevertebral muscles compared to sham surgery. This implantable biomaterial platform reduces local postoperative inflammation with potential surgical applications throughout the body.

The rational design of self-assembled compounds is crucial for the highly efficient development of carrier-free nanomedicines. Herein, based on computer-aided strategies, important physicochemical properties are identified to guide the rational design of self-assembled compounds. Then, the pharmacophore hybridization strategy is used to design self-assemble nanoparticles by preparing new chemical structures by combining pharmacophore groups of different bioactive compounds. Hydroxychloroquine is grafted with the lipophilic vitamin E succinate and then co-assembled with bortezomib to fabricate the nanoparticle. The nanoparticle can reduce M2-type tumor-associated macrophages (TAMs) through lysosomal alkalization and induce immunogenic cell death (ICD) and nuclear factor-κB (NF-κB) inhibition in tumor cells. In mouse models, the nanoparticles induce decreased levels of M2-type TAMs, regulatory T cells, and transforming growth factor-β (TGF-β), and increase the proportion of cytotoxicity T lymphocytes. Additionally, the nanoparticles reduce the secretion of Interleukin-6 (IL-6) by inhibiting NF-κB and enhance the programmed death ligand-1 (PD-L1) checkpoint blockade therapy. The pharmacophore hybridization-derived nanoparticle provides a dual-modulation strategy to reprogram the tumor microenvironment, which will efficiently enhance the chemoimmunotherapy against triple-negative breast cancer.

The complex composition of traditional Chinese medicines (TCMs) has posed challenges for in-depth study and global application, despite their abundance of bioactive compounds that make them valuable resources for disease treatment. To overcome these obstacles, it is essential to modernize TCMs by focusing on precise disease treatment. This involves elucidating the structure-activity relationships within their complex compositions, ensuring accurate in vivo delivery, and monitoring the delivery process. This review discusses the research progress of TCMs in precision disease treatment from three perspectives: spatial multi-omics technology for precision therapeutic activity, carrier systems for precise in vivo delivery, and medical imaging technology for visualizing the delivery process. The aim is to establish a novel research paradigm that advances the precision therapy of TCMs.

Liver ischemia and reperfusion (I/R) injury is a reactive oxygen species (ROS)-related disease that occurs during liver transplantation and resection and hinders postoperative liver function recovery. Current approaches to alleviate liver I/R injury have limited effectiveness due to the short circulation time, poor solubility, and severe side effects of conventional antioxidants and anti-inflammatory drugs. Herein, a universal strategy is proposed to fabricate a Trojan horse-like biohybrid nanozyme (THBN) with hepatic-targeting capabilities. Tannic acid (TA) mediates adeno-associated virus (AAV8) decoration onto 2D Ti₃C₂ nanosheets, resulting in THBN with a size of 116.2 ± 9.5 nm. Remarkably, THBN exhibits catalase (CAT)-like activity, broad-spectrum ROS scavenging activity and targeted delivery to liver tissue owing to the presence of AAV8. Both in vivo and in vitro experiments confirmed the efficacy of THBN in attenuating liver I/R injury by mitigating inflammation and oxidative stress and inhibiting hepatocellular apoptosis. RNA-seq analysis suggests that THBN may alleviate liver I/R injury by activating the PKC pathway. The effective targeting and therapeutic capabilities of THBN represent an advancement in nanotherapeutics for hepatic ischemia‒reperfusion injury, shedding light on the promising potential of this next-generation nanotherapeutic approach.